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Purine Nucleoside Mediated Neuroprotection in the 6-Hydroxydopamine Rodent Model of Parkinson's Disease

Terpstra, Brian T.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1298395215

Abstract Details

2011, PhD, University of Cincinnati, Medicine: Neuroscience/Medical Science Scholars Interdisciplinary.
Parkinson’s Disease (PD) is a progressive, neurodegenerative disorder characterized by bradykinesia, akinesia, and resting tremor. While dopamine replacement therapy effectively eliminates symptoms in the early stages, as the disease progresses, therapeutic effects lessen and side effects emerge. The lack of long-term therapies highlights the need for compounds that slow the progression of the disease. Inosine is neuroprotective in models of stroke and nerve transection; however, its effect in a model of PD has not been investigated. Chapter 1 examined the neuroprotective potential of peripherally administered inosine in the 6-hydroxydopamine rodent model of PD. These experiments show that inosine is both neurotrophic and neuroprotective in vitro. Peripheral inosine treatment increased nigral and striatal inosine levels and protected nigral dopamine neurons against intrastriatal 6-hydroxydopamine infusion. Peripherally administered inosine is extensively metabolized. Chapter 2 determined the compound responsible for inosine-mediated neuroprotection in the 6-hydroxydopamine rodent model of PD by inhibiting the enzymatic metabolism of inosine. The results of this study show that inhibiting the final step in rodent inosine metabolism (uric acid→allantoin) abolished the functional and morphological neuroprotection seen with systemic inosine treatment. Systemic allantoin treatment resulted in a level of neuroprotection similar to that seen with systemic inosine, indicating that allantoin is responsible for inosine-mediated neuroprotection. To confirm that allantoin is responsible for inosine-mediated neuroprotection, Chapter 3 examined the levels of plasma purines following systemic inosine, inosine/potassium oxonate (urate oxidase inhibitor; KOx) and allantoin. These results showed that inosine and allantoin administration both significantly elevated allantoin, without altering any other plasma purines. Concurrent administration of KOx significantly reduced the increase in plasma allantoin following inosine treatment. These results confirm that allantoin is responsible for inosine-mediated neuroprotection in our model. The 6-hydroxydopamine rodent model of PD requires direct intracerebral infusion, severely compromising the blood brain barrier (BBB). To determine the bioavailability of peripheral allantoin, Chapter 4 examined the effects of subcutaneous (s.c.) and oral allantoin on plasma and whole brain levels of allantoin in animals with intact BBBs. Both s.c. and oral allantoin significantly elevated plasma allantoin, but only s.c. allantoin significantly elevated whole brain allantoin. These results show that allantoin may be a viable peripherally administered treatment in PD. Oxidative stress is thought to play a role in the current model and previous evidence (Gus’kov et al., 2001 and 2004) shows antioxidant effects of systemic allantoin, therefore we sought to determine appropriate markers of oxidative stress for our model. Chapter 5 determined the effects of our lesion on levels of protein carbonyls and Thiobarbituric Acid Reactive Substances (TBARs) in the striatum 24 hours post-lesion. Our lesion had no effect on protein carbonyls or TBARs. Chapter 6 examined the effect of systemic allantoin on NADPH oxidase-1 immunoreactivity (NOX-1ir). Allantoin treatment decreased the number of NOX-1ir cells in the SN and the central gray. The current results demonstrate allantoin’s potential to be a systemically administered, non-invasive therapy for PD. The effect of allantoin on NOX-1ir cells suggests that allantoin may reduce oxidative stress and be able to modify the underlying disease process of PD.
Timothy Collier, PhD (Committee Chair)
Caryl Sortwell, PhD (Committee Member)
Jack Lipton, PhD (Committee Member)
Kim Seroogy, PhD (Committee Member)
Kathy Steece-Collier, PhD (Committee Member)
202 p.
Neurology
Parkinson's Disease; Inosine; Allantoin; Uric Acid; Oxidative Stress

Recommended Citations

Citations

  • Terpstra, B. T. (2011). Purine Nucleoside Mediated Neuroprotection in the 6-Hydroxydopamine Rodent Model of Parkinson's Disease [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1298395215

    APA Style (7th edition)

  • Terpstra, Brian. Purine Nucleoside Mediated Neuroprotection in the 6-Hydroxydopamine Rodent Model of Parkinson's Disease. 2011. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1298395215.

    MLA Style (8th edition)

  • Terpstra, Brian. "Purine Nucleoside Mediated Neuroprotection in the 6-Hydroxydopamine Rodent Model of Parkinson's Disease." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1298395215

    Chicago Manual of Style (17th edition)

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